Water-soluble benzoazepine compound and its pharmaceutical composition

ABSTRACT

The present invention provides a benzoazepine compound represented by following general formula (1): 
     
       
         
         
             
             
         
       
     
     or a salt thereof,
 
wherein R represents a hydrogen atom, a hydroxy group optionally protected with a protecting group, etc., R 1  represents a hydrogen atom or hydroxy-protecting group, and X represents an oxygen atom or a sulfur atom. The benzoazepine compound of the present invention and salts thereof have high solubility in water, and can be suitably used for injections.

TECHNICAL FIELD

The present invention relates to a novel benzoazepine compound and itspharmaceutical composition.

BACKGROUND OF ART

Tolvaptan represented by the following formula (2) is a known compound,and has been disclosed in, for example, U.S. Pat. No. 5,258,510specification (Example 1199).

It is known that tolvaptan is useful as a vasopressin antagonist havingaquaretic activity (Circulation, 107, pp. 2690-2696 (2003)). However,because of its low water solubility, tolvaptan has problems in that itis poorly absorbed by the intestinal canal, its dosage form andadministration route are limited, etc. Although attempts have been madeto solve these problems so that, for example, tolvaptan can beadministered in the form of an amorphous solid preparation composition(Japanese Unexamined Patent Publication No. 1999-21241), in theapplication of tolvaptan, its dosage form and administration route stillremain limited.

DISCLOSURE OF THE INVENTION

The present invention aims to provide a novel benzoazepine compound forimproving the solubility of tolvaptan in water.

The present inventors conducted extensive research to solve the aboveproblem, and as a result found that when tolvaptan is in the form of aphosphate ester compound, the water solubility thereof can be remarkablyimproved.

The present invention has been accomplished based on this finding.

Specifically, the present invention provides the following benzoazepinecompounds, and compositions comprising the same, as described in Item 1to 13 below.

Item 1. A benzoazepine compound represented by general formula (1)

or a salt thereof,

wherein R represents a hydrogen atom, a hydroxy group optionallyprotected with a protecting group, a mercapto group optionally protectedwith a protecting group, or an amino group optionally protected with oneor two protecting groups; R¹ represents a hydrogen atom or ahydroxy-protecting group; and X represents an oxygen atom or a sulfuratom.

Item 2. A benzoazepine compound according to item 1 or a salt thereof,wherein X is an oxygen atom.

Item 3. A benzoazepine compound according to item 1 or 2, or a saltthereof, wherein R is a hydroxy group optionally protected with aprotecting group.

Item 4. A benzoazepine compound according to item 1 or 2, or a saltthereof, wherein R is a hydrogen atom, a mercapto group optionallyprotected with a protecting group, or an amino group optionallyprotected with one or two protecting groups.

Item 5. A benzoazepine compound according to any one of items 1, 2, 3and 4, or a salt thereof, wherein R¹ is a hydroxy-protecting group.

Item 6. A benzoazepine compound according to any one of items 1, 2, 3and 4, or a salt thereof, wherein R¹ is a hydrogen atom.

Item 7. A benzoazepine compound according to item 1 or a salt thereof,wherein X is a sulfur atom.

Item 8. A benzoazepine compound according to item 1 or a salt thereof,wherein X is an oxygen atom, R is a hydroxy group, and R¹ is a hydrogenatom.

Item 9. A pharmaceutical composition comprising a benzoazepine compoundof item 1 or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable diluent and/or carrier.

Item 10. A pharmaceutical composition according to item 9, for use as avasodilator, hypotensor, aquaretic agent, PKD, or platelet aggregationinhibitor.

Item 11. An aqueous solution composition comprising a benzoazepinecompound of item 1 or a pharmaceutically acceptable salt thereof.

Item 12. An aqueous solution composition according to item 11,comprising a benzoazepine compound of item 1 or a pharmaceuticallyacceptable salt thereof, together with a buffer, isotonizing agent andinjection solvent, and which is in the form of an injection.

Item 13. An aqueous solution composition according to item 12, furthercomprising a pH adjuster.

“Lower” as used herein indicates C₁₋₆ unless otherwise noted.

Examples of protecting groups for a “hydroxy group optionally protectedwith a protecting group”, “mercapto group optionally protected with aprotecting group” and “hydroxy-protecting group” include lower alkylgroups, phenyl(lower)alkyl groups, cyano lower alkyl groups, and loweralkyloxycarbonyl lower alkyl groups.

Examples of protecting groups for an “amino group optionally protectedwith one or two protecting groups” include lower alkyl groups optionallybearing hydroxy group(s).

Examples of lower alkyl groups and lower alkyl groups inphenyl(lower)alkyl groups, cyano lower alkyl groups, loweralkyloxycarbonyl lower alkyl groups, and lower alkyl groups optionallybearing hydroxy group(s) include C₁₋₆ straight or branched alkyl groups,for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,isohexyl, 3-methylpentyl, and the like.

Preferable phenyl(lower)alkyl groups are, for example, benzyl,phenethyl, 3-phenylpropyl, trityl, etc.

Preferable cyano lower alkyl groups are C₁₋₆ straight or branched alkylgroups substituted with one to three cyano groups, for example,cyanomethyl, 2-cyanoethyl, 1-, 2-, or 3-cyano-n-propyl, 1-, 2-, or3-cyano-isopropyl, 1-, 2-, 3-, or 4-cyano-n-butyl, 1-, 2-, 3-, or4-cyano-isobutyl, 1-, 2-, 3-, or 4-cyano-tert-butyl, 1-, 2-, 3-, or4-cyano-sec-butyl, 1-, 2-, 3-, 4-, or 5-cyano-n-pentyl, 1-, 2-, 3-, 4-,or 5-cyano-isopentyl, 1-, 2-, 3-, 4-, or 5-cyano-neopentyl, 1-, 2-, 3-,4-, 5-, or 6-cyano-n-hexyl, 1-, 2-, 3-, 4-, 5-, or 6-cyano-isohexyl, 1-,2-, 3-, 4-, 5-, or 6-cyano-3-methylpentyl, and the like.

Preferable lower alkyloxycarbonyl lower alkyl groups arealkyloxycarbonylalkyl groups wherein the alkyloxy moiety is a C₁₋₆straight or branched alkyloxy group and the alkyl moiety is a C₁₋₆straight or branched alkyl group, for example, methoxycarbonylmethyl,ethoxycarbonylmethyl, n-propoxycarbonylmethyl, isopropoxycarbonylmethyl,n-butoxycarbonylmethyl, isobutoxycarbonylmethyl,n-pentoxycarbonylmethyl, n-hexyloxycarbonylmethyl,2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 4-methoxycarbonylbutyl,5-methoxycarbonylpentyl, 6-methoxycarbonylhexyl, and the like.

Preferable lower alkyl groups optionally bearing hydroxy group(s) areC₁₋₆ straight or branched alkyl groups optionally substituted with oneto three hydroxy groups, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, hydroxymethyl,2-hydroxyethyl, 1-, 2-, or 3-hydroxy-n-propyl, 1-, 2-, or3-hydroxy-isopropyl, 1-, 2-, 3-, or 4-hydroxy-n-butyl, 1-, 2-, 3-, or4-hydroxy-isobutyl, 1-, 2-, 3-, or 4-hydroxy-tert-butyl, 1-, 2-, 3-, or4-hydroxy-sec-butyl, 1-, 2-, 3-, 4-, or 5-hydroxy-n-pentyl, 1-, 2-, 3-,4-, or 5-hydroxy-isopentyl, 1-, 2-, 3-, 4-, or 5-hydroxy-neopentyl, 1-,2-, 3-, 4-, 5-, or 6-hydroxy-n-hexyl, 1-, 2-, 3-, 4-, 5-, or6-hydroxy-isohexyl, 1-, 2-, 3-, 4-, 5-, or 6-hydroxy-3-methylpentyl, andthe like.

Preferable amino groups optionally substituted with one or twoprotecting group(s) are amino groups optionally bearing one or two C₁₋₆straight or branched alkyl groups optionally bearing one to threehydroxy groups, for example, amino, methylamino, dimethylamino,ethylamino, diethylamino, n-propylamino, di-n-propylamino,iso-propylamino, di-iso-propylamino, n-butyl amino, di-n-butylamino,iso-butyl amino, di-so-butylamino, tert-butyl amino, di-tert-butylamino,n-pentyl amino, di-n-pentylamino, n-hexyl amino, di-n-hexylamino,hydroxymethylamino, 2-hydroxyethylamino, diethylamino,di-(2-hydroxyethyl)amino, 3-hydroxypropylamino, 4-hydroxybutyl amino,and the like.

Among benzoazepine compounds represented by the above general formula(1), the following compounds and salts thereof are preferable:

when X is an oxygen atom,

(1) compounds wherein R is a hydroxy group and R¹ is a hydrogen atom,

(2) compounds wherein R is a hydroxy group and R¹ is ahydroxy-protecting group,

(3) compounds wherein R is a mercapto group and R¹ is ahydroxy-protecting group, and

(4) compounds wherein R is an amino group protected with one or twoprotecting groups, and R¹ is a hydroxy-protecting group; and

when X is a sulfur atom,

(1) compounds wherein R is an hydroxy group and R¹ is a hydrogen atom orhydroxy-protecting group.

Particularly preferable of these is the compound wherein X is an oxygenatom, R is a hydroxy group, and R¹ is a hydrogen atom; or a saltthereof.

Benzoazepine compounds represented by the above general formula (1) canbe produced by various methods, and an example thereof is a method asshown by the following reaction schemes 1 to 7:

wherein R³ and R⁴ are independently a lower alkyl group oroptionally-substituted phenyl group, or R³ and R⁴ may instead be linkedtogether through or without one or more additional heteroatoms to form,together with the nitrogen atom to which they are bound, a 5- to8-membered saturated or unsaturated ring; and R^(1a) and R^(2a) may bethe same or different, and each represents a hydroxy-protecting group.

Examples of lower alkyl groups are as mentioned above, including C₁₋₆straight or branched alkyl groups, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, and the like.

Examples of substituents for optionally-substituted phenyl groupsinclude lower alkyl groups as above; C₁₋₆ straight or branched alkoxygroups, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, and the like; and halogen atoms, forexample, fluorine, chlorine, bromine, iodine, and the like.

Preferable examples of optionally-substituted phenyl groups includephenyl; 2-, 3- or 4-methylphenyl; 2-, 3- or 4-chlorophenyl; 2-, 3-, or4-methoxyphenyl; etc.

Examples of 5- to 8-membered saturated or unsaturated rings formed by R³and R⁴ being linked together include morpholine ring, etc.

Compound (4) can be produced by reacting compound (2) with compound (3)in a suitable solvent in the presence of acid.

Examples of solvents include halogenated hydrocarbon solvents, forexample, methylene chloride, chloroform, 1,2-dichloroethane, carbontetrachloride, and the like; esters, for example, ethyl acetate and thelike; aromatic hydrocarbons, for example, benzene, toluene, xylene, andthe like; acetonitrile; etc.

Examples of acids include mild acids, for example, 1H-tetrazole,5-methyltetrazole, pyridinium hydrobromide, and the like.

The amount of acid is usually at least about 1 mole, and preferablyabout 1 to about 10 moles, per mol of compound (2).

The amount of compound (3) is usually 0.5 to 2 moles, and preferably 0.7to 1.5 moles, per mol of compound (2).

The reaction temperature is usually −20 to 50° C., preferably 0 to 50°C., and more preferably 0° C. to room temperature. The reaction time isusually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, andmore preferably 1 to 3 hours.

Compound (1a) can be produced by reacting compound (4) with an oxidizingagent in a suitable solvent.

Examples of solvents include halogenated hydrocarbon solvents, forexample, methylene chloride, chloroform, 1,2-dichloroethane, carbontetrachloride, and the like; esters, for example, ethyl acetate and thelike; aromatic hydrocarbons, for example, benzene, toluene, xylene, andthe like; acetonitrile; etc.

Examples of oxidizing agents include peracids, for example, hydrogenperoxide, and metachloroperbenzoic acid, peracetic acid, permaleic acid,and the like.

The amount of oxidizing agent is usually at least about 1 mole, andpreferably about 1 to about 3 moles, per mol of compound (4).

The reaction temperature is usually −100 to 50° C., preferably −40° C.to room temperature, and more preferably −40 to 0° C. The reaction timeis usually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, andmore preferably 30 minutes to 2 hours.

Compound (1b) can be obtained by deprotecting the protected hydroxygroups of compound (1a) by routine methods.

When, for example, the hydroxy-protecting groups are lower alkyl groups,deprotection can be performed under routine hydrolysis conditions.

Such hydrolysis is preferably performed in the presence of base or acid(including Lewis acid).

A wide range of known inorganic and organic bases can be used as such abase. Preferable inorganic bases are, for example, alkali metals (e.g.,sodium, potassium, etc.); alkaline earth metals (e.g., magnesium,calcium, etc.); and their hydroxides, carbonates and hydrogencarbonates.Preferable organic bases are, for example, trialkylamines (e.g.,trimethylamine, triethylamine, etc.), picoline, and1,5-diazabicyclo[4,3,0]non-5-ene.

A wide range of known organic and inorganic acids can be used as such anacid. Preferable organic acids are fatty acids, for example, formicacid, acetic acid, propionic acid, and the like; and trihaloaceticacids, for example, trichloroacetic acid, trifluoroacetic acid, and thelike. Preferable inorganic acids are, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide,etc. Examples of Lewis acids include boron trifluoride ether complex,boron tribromide, aluminium chloride, ferric chloride, etc.

When a trihaloacetic acid or Lewis acid is used, the hydrolysis ispreferably performed in the presence of cation scavenger (e.g., anisole,phenol, etc).

The amount of base or acid is not limited so long as it satisfieshydrolysis requirements.

The reaction temperature is usually −20 to 100° C., preferably 0 to 50°C., and more preferably 0° C. to room temperature. The reaction time isusually 5 minutes to 24 hours, preferably 15 minutes to 6 hours, andmore preferably 15 minutes to 3 hours.

When, for example, the hydroxy-protecting groups are phenyl(lower)alkylgroups, deprotection can be preformed by a routine catalytic reduction.

Catalysts suitable for such catalytic reduction are platinum catalysts(e.g., platinum plate, spongy platinum, platinum black, colloidalplatinum, platinum oxide, platinum wire, etc.), palladium catalysts(e.g., spongy palladium, palladium black, palladium oxide, palladiumcarbon, palladium/barium sulfate, palladium/barium carbonate, etc.),nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel,etc.), cobalt catalysts (e.g., reduced cobalt, Raney cobalt, etc.), ironcatalysts (e.g., reduced iron, etc.), and the like. When a palladiumcarbon catalyst is used, the catalytic reduction is preferably performedin the presence of zinc bromide.

The amount of catalyst used for the catalytic reduction is not limited,and may be a routine amount.

The reaction temperature is usually 0 to 100° C., preferably 0 to 50°C., and more preferably room temperature to 50° C. The reaction time isusually 5 minutes to 24 hours, preferably 5 minutes to 3 hours, and morepreferably 5 minutes to 1 hour.

Compound (2) is reacted with phosphorus oxychloride, and then hydrolyzedto give compound (1b).

The amount of phosphorus oxychloride is usually 1 mole to large excess,and preferably 1 to 5 moles, per mol of compound (2).

The above reaction is carried out in the presence of basic compound in asuitable solvent.

Examples of solvents for the reaction with phosphorus oxychlorideinclude ethers, for example, diethyl ether, dioxane, tetrahydrofuran,monoglyme, diglyme, and the like; halogenated hydrocarbon solvents, forexample, methylene chloride, chloroform, 1,2-dichloroethane, carbontetrachloride, and the like; esters, for example, ethyl acetate and thelike; aromatic hydrocarbons, for example, benzene, toluene, xylene, andthe like; acetonitrile; etc.

Examples of basic compounds include carbonates, for example, sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, cesium carbonate, and the like; alkali metal hydroxides,for example, sodium hydroxide, potassium hydroxide, and the like; alkaliearth metal hydroxides, for example, calcium hydroxide and the like;phosphates, for example, potassium phosphate, sodium phosphate, and thelike; organic bases, for example, pyridine, imidazole,N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), and the like; and mixtures thereof.

The amount of basic compound is usually at least about 3 moles, andpreferably about 3 to about 10 moles, per mol of compound (2). Thereaction temperature is usually −100 to 50° C., preferably −50° C. toroom temperature, and more preferably −30° C. to room temperature. Thereaction time is usually 15 minutes to 24 hours, preferably 30 minutesto 6 hours, and more preferably 1 to 3 hours.

Hydrolysis can be achieved by adding water to the above reaction mixtureor adding the reaction mixture to water.

Because this is usually accompanied by excess reagent decomposition andheat is thereby generated, hydrolysis is preferably carried out withcooling. To complete the reaction, heating is preferably carried outafter the initial reaction has subsided.

The reaction time is usually 15 minutes to 24 hours, preferably 30minutes to 6 hours, and more preferably 1 to 3 hours.

wherein R¹ is the same as above.

Compound (2) is reacted with diphenyl phosphite, and then reacted withan alcohol (R¹OH) to give compound (1c).

The amount of diphenyl phosphite is usually 1 mole to large excess, andpreferably 1 to 5 moles, per mol of compound (2). The amount of alcohol(R¹⁰H) is usually 1 mole to large excess, and preferably 1 to 10 moles,per mol of compound (2).

The above reaction is carried out in the presence of basic compound in asuitable solvent.

Examples of solvents include ethers, for example, diethyl ether,dioxane, tetrahydrofuran, monoglyme, diglyme, and the like; halogenatedhydrocarbon solvents, for example, methylene chloride, chloroform,1,2-dichloroethane, carbon tetrachloride, and the like; esters, forexample, ethyl acetate and the like; aromatic hydrocarbons, for example,benzene, toluene, xylene, and the like; and acetonitrile.

Examples of basic compounds include carbonates, for example, sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, caesium carbonate, and the like; alkali metal hydroxides,for example, sodium hydroxide, potassium hydroxide, and the like; alkaliearth metal hydroxides, for example, calcium hydroxide and the like;phosphates, for example, potassium phosphate, sodium phosphate, and thelike; organic bases, for example, pyridine, imidazole,N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), and the like; and mixtures thereof.

The amount of basic compound is usually at least about 1 mole, andpreferably about 1 to about 10 moles, per mol of compound (2). Organicsolvents may also be used as solvent.

The reaction temperature is usually −100 to 50° C., preferably −50° C.to room temperature, and more preferably −30° C. to room temperature.The reaction time is usually 15 minutes to 24 hours, preferably 30minutes to 6 hours, and more preferably 1 to 3 hours.

wherein R¹ is the same as above.

Oxidization of phosphite can be carried out using about 1 to about 3equivalents of phosphorous acid-oxidizing agent, at a temperature in therange of about 0° C. to about 50° C. Preferably, the reaction is carriedout using about 5 to about 15% excess phosphorous acid-oxidizing agentat 0° C. to room temperature.

A phosphorous acid-oxidizing agent is a reagent that oxidizes aphosphite to a phosphate. Examples thereof include peroxides, forexample, hydrogen peroxide; metachloroperbenzoic acid and the like;iodine in water; bromine; nitrogen tetroxide; etc. Iodine in water ispreferable.

The above reaction is carried out in a suitable solvent.

Examples of solvents include ethers, for example, diethyl ether,dioxane, tetrahydrofuran, monoglyme, diglyme, and the like; halogenatedhydrocarbon solvents, for example, methylene chloride, chloroform,1,2-dichloroethane, and the like; esters, for example, ethyl acetate andthe like; aromatic hydrocarbons, for example, benzene, toluene, xylene,and the like; acetonitrile; and pyridine.

The reaction temperature is usually −100 to 50° C., preferably −50° C.to room temperature, and more preferably −30° C. to room temperature.The reaction time is usually 15 minutes to 24 hours, preferably 15minutes to 6 hours, and more preferably 15 minutes to 3 hours.

wherein R¹ is the same as above; and R¹¹ and R¹² may the same ordifferent, and each represents a hydrogen atom or a lower alkyl groupoptionally bearing hydroxy group(s).

Amine (R¹¹R¹²NH) and carbon tetrachloride are reacted with phosphorousacid diester (1c) to give phosphoroamidite (1e).

Sodium hypochlorite may also be used in place of carbon tetrachloride.

The amount of carbon tetrachloride is usually 1 mole to large excess,and preferably 1 to 5 moles, per mol of compound (1c). The amount ofamine (R¹¹R¹²NH) is usually 1 mole to large excess, and preferably 1 to10 moles, per mol of compound (1c).

The above reaction is carried out in the presence of basic compound in asuitable solvent.

Examples of solvents include ethers, for example, diethyl ether,dioxane, tetrahydrofuran, monoglyme, diglyme, and the like; halogenatedhydrocarbon solvents, for example, methylene chloride, chloroform,1,2-dichloroethane, carbon tetrachloride, and the like; esters, forexample, ethyl acetate, and the like; aromatic hydrocarbons, forexample, benzene, toluene, xylene, and the like; acetonitrile; etc.

Examples of basic compounds include carbonates, for example, sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, caesium carbonate, and the like; alkali metal hydroxides,for example, sodium hydroxide, potassium hydroxide, and the like; alkaliearth metal hydroxides, for example, calcium hydroxide and the like;phosphates, for example, potassium phosphate, sodium phosphate, and thelike; organic bases, for example, pyridine, imidazole,N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine,trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), and the like; and mixtures thereof. The amount of basiccompound is usually at least about 1 mole, and preferably about 1 to 10about moles, per mol of compound (2). Organic solvents may also be usedas solvent.

The reaction temperature is usually −100 to 50° C., preferably −50° C.to room temperature, and more preferably −30° C. to room temperature.The reaction time is usually 1 minute to 24 hours, preferably 1 minuteto 6 hours, and more preferably 1 minute to 3 hours.

wherein R¹ is the same as above.

Phosphorous acid diester (1c) is reacted with sulfur to givephosphorothioic acid diester (1f).

The amount of sulfur usually 1 mole to large excess, and preferably 1 to5 moles, per mol of compound (1c).

The above reaction is carried out in the presence of basic compound in asuitable solvent.

Examples of solvents include ethers, for example, diethyl ether,dioxane, tetrahydrofuran, monoglyme, diglyme, and the like; halogenatedhydrocarbon solvents, for example, methylene chloride, chloroform,1,2-dichloroethane, and the like; esters, for example, ethyl acetate andthe like; aromatic hydrocarbons, for example, benzene, toluene, xylene,and the like; acetonitrile; and pyridine.

Examples of basic compounds include carbonates, for example, sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, caesium carbonate, and the like; alkali metal hydroxides,for example, sodium hydroxide, potassium hydroxide, and the like; alkaliearth metal hydroxides, for example, calcium hydroxide and the like;phosphates, for example, potassium phosphate, sodium phosphate, and thelike; alkali metal hydrides, for example, sodium hydride, potassiumhydride, and the like; alkali metals, for example, potassium, sodium,and the like; sodium amide; metal alcoholates, for example, sodiummethylate, sodium ethylate, sodium n-butoxide, sodium tert-butoxide,potassium tert-butoxide, and the like; organic bases, for example,pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), and the like; and mixtures thereof. The amount of basiccompound is usually at least about 1 mole, and preferably about 1 toabout 10 moles, per mol of compound (2). Organic solvents may also beused as solvent.

The reaction temperature is usually −100 to 50° C., preferably −50° C.to room temperature, and more preferably −30° C. to room temperature.The reaction time is usually 15 minutes to 24 hours, preferably 30minutes to 6 hours, and more preferably 1 to 3 hours.

wherein R^(1′) is a hydroxy-protecting group.

The protecting group of compound (1g), which is a compound (1f) obtainedby reaction scheme 6 wherein R¹ is a hydroxy-protecting group, isremoved to give compound (1 h).

When R¹ is a cyanoethyl group, the protecting group can be removed byusing a basic compound.

The above reaction is carried out in the presence of basic compound in asuitable solvent.

Examples of solvents include water; alcohols, for example, methanol,ethanol, isopropyl alcohol, and the like; ethers, for example, diethylether, dioxane, tetrahydrofuran, monoglyme, diglyme, and the like;halogenated hydrocarbon solvents, for example, methylene chloride,chloroform, 1,2-dichloroethane, carbon tetrachloride, and the like;esters, for example, ethyl acetate and the like; aromatic hydrocarbons,for example, benzene, toluene, xylene, and the like; aprotic polarsolvents, for example, dimethylformamide (DMF), dimethylsulfoxide(DMSO), and the like; ketones, for example, acetone, methyl ethylketone, methyl isobutyl ketone, and the like; acetonitrile; and mixturesthereof.

Examples of basic compounds include carbonates, for example, sodiumcarbonate, potassium carbonate, sodium bicarbonate, potassiumbicarbonate, caesium carbonate, and the like; alkali metal hydroxides,for example, sodium hydroxide, potassium hydroxide, and the like; alkaliearth metal hydroxides, for example, calcium hydroxide and the like;phosphates, for example, potassium phosphate, sodium phosphate, and thelike; alkali metal hydrides, for example, sodium hydride, potassiumhydride, and the like; alkali metals, for example, potassium, sodium,and the like; sodium amide; metal alcoholates, for example, sodiummethylate, sodium ethylate, sodium n-butoxide, sodium tert-butoxide,potassium tert-butoxide, and the like; organic bases, for example,pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine,triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), and the like; and mixtures thereof. The amount of basiccompound is usually at least about 1 mole, and preferably about 1 toabout 10 moles, per mol of compound (2). Organic solvents may also beused as solvent.

The reaction temperature is usually −100 to 50° C., preferably −50° C.to room temperature, and more preferably −30° C. to room temperature.The reaction time is usually 15 minutes to 24 hours, preferably 30minutes to 6 hours, and more preferably 1 to 3 hours.

Compounds (2), (3), (4), (1a), (1b), (1c), (1d), (1e), (1f), (1g) and (1h) in the above reaction schemes may be suitable salts thereof. Examplesof such suitable salts include the same kinds of salts as with compound(1).

Compounds obtained according to the above reaction schemes can beisolated and purified from the reaction mixture by conventional manners,for example, after cooling the reaction mixture, isolating crudereaction product by filtration, concentration, extraction or likeisolation procedure, and then purifying the resultant by columnchromatography, recrystallization or like routine purificationprocedure.

Compounds represented by general formula (1) of the present inventioninclude stereoisomers, optical isomers, and solvates (hydrates,ethanolates, etc.) thereof.

Examples of salts of compounds represented by general formula (1) of thepresent invention include pharmaceutically acceptable salts for example,metal salts, for example, alkali metal salts (e.g., sodium salts,potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts,magnesium salts, etc.) and the like; ammonium salts; organic base salts(e.g., trimethylamine salts, triethylamine salts, pyridine salts,picoline salts, dicyclohexylamine salts, ethylenediamine salts,N,N′-dibenzylethylenediamine salts, tris(hydroxymethyl)aminomethanesalts, ethanolamine salts, etc.); etc. Among these, alkali metal saltsare preferable, and sodium salts are more preferable.

Such salts can be easily formed by applying, to the compound of thepresent invention, the corresponding pharmaceutically acceptable basiccompound. Examples of applicable basic compounds include sodiumhydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate,potassium hydrogencarbonate, etc.

The compound of the present invention has, for example, vasopressinantagonism, vasodilating activity, hypotensive activity, activity forinhibiting saccharide release in liver, mesangial cell growth inhibitoryactivity, aquaretic activity, and platelet aggregation inhibitoryactivity. The compound is useful as a vasodilator, hypotensor, aquareticagent and platelet aggregation inhibitor, and is effective in theprevention and treatment of hypertension, edema (e.g., cardiac edema,hepatic edema, renal edema, cerebral edema), abdominal dropsy, heartfailure (e.g., severe heart failure), renal dysfunction, syndrome ofinappropriate secretion of vasopressin (SIADH), liver cirrhosis,hyponatremia, hypokalemia, diabetes, circulatory insufficiency,polycystic kidney disease (PKD), cerebral infarction, myocardialinfarction, and the like.

When administered to the human body as a medicine, the compound of thepresent invention may be used simultaneously or separately with othervasopressin antagonists, ACE inhibitors, β-blocking agents, aquareticagents, angiotensin II antagonists (ARB), digoxin, and/or likepharmaceutical drugs.

The compound of the present invention is usually used in the form of ageneral pharmaceutical composition. Such a pharmaceutical compositioncan be prepared by a conventional method using diluents and/orexcipients which are commonly used, for example, fillers, expanders,binders, moisturizers, disintegrators, surfactants, lubricants, etc.

The form of the pharmaceutical composition containing the compound ofthe present invention can be suitably selected depending on the purposeof the treatment. It may be in the form of, for example, a tablet, pill,powder, solution, suspension, emulsion, capsule, suppository, ointment,or granules. An aqueous solution composition, for example, injection,instillation, and the like is particularly preferable.

When, for example, preparing an injection by using the compound of thepresent invention, such an injection is preferably formulated into asolution, emulsion, or suspension that has been sterilized and isisotonic with blood. For preparing such a solution, emulsion orsuspension using the compound of the present invention, any diluentscommonly employed in this field may be used. Examples of such diluentsinclude water, aqueous lactic acid solutions, ethyl alcohol, propyleneglycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,and polyoxyethylene sorbitan fatty acid esters. Further, in this case,sodium chloride, glucose, mannitol, glycerol and the like isotonizingagents in amounts sufficient to prepare an isotonic solution may bemixed in the pharmaceutical composition. Ordinary pH adjusters,solubilizers, buffers, soothing agents and the like may also be added.

An injection containing the compound of the present invention can beprepared by a conventional method, using a compound represented bygeneral formula (1) or pharmaceutically acceptable salt thereof,together with a buffer, isotonizing agent, injection solvent, and, ifnecessary, pH adjuster.

Examples of buffers include carbonates, borates, phosphates, citrates,tris(hydroxymethyl)aminomethane, malates, and tartrates. It is alsopossible to singly use an acid or base forming such a buffer.

Examples of pH adjusters include basic compounds, for example, sodiumhydroxide and the like; acids, for example, hydrochloric acid and thelike.

Further, colorants, preservatives, fragrances, flavorings, sweeteners,and the like, as well as other medicines, can also be mixed in thepharmaceutical composition, as necessary.

The content of the compound represented by general formula (1) of thepresent invention or a salt thereof in the pharmaceutical composition isnot limited, and can be suitably selected from a wide range. The contentis usually 0.01 to 70 wt % of the pharmaceutical composition.

The method for administering such a pharmaceutical composition is notlimited, and it may be administered by a suitable method depending onthe form of the pharmaceutical composition; the patient's age, gender,etc.; the degree of the patient's symptoms; and the like. For example,tablets, pills, solutions, suspensions, emulsions, granules and capsulesmay be orally administered. Injections may be administered byintravenous injection, alone or as a mixture with glucose, amino acidand/or like ordinary replenishers. Injections may also be given alone byintramuscular, intracutaneous, subcutaneous or intraperitonealadministration, as necessary.

The dose of the pharmaceutical composition of the present invention canbe selected depending on the usage; the patient's age, gender, etc.; thedegree of the disease; and the like. The dose is usually such that thecompound represented by general formula (1), which is an effectiveingredient, is administered in an amount of 0.001 to 100 mg, andpreferably 0.001 to 50 mg, per 1 kg of body weight per day in one ormore administrations.

The dose varies with various conditions. A dose smaller than the aboverange may be sufficient, while a dose larger than the above range may benecessary.

The patents, patent applications, and documents cited herein areincorporated by reference.

EFFECT OF THE INVENTION

Compound (1) of the present invention or a salt thereof has remarkablyexcellent water solubility, excellent absorbability, etc.

Compound (1b) in particular or a salt thereof has remarkably excellentwater solubility, excellent absorbability, etc.

When administered into the human body, compound (1) of the presentinvention or a salt thereof, compound (1b) or a salt thereof inparticular, enables the easy generation of the active ingredienttolvaptan.

Further, compound (1) of the present invention or a salt thereof can beeasily crystallized and is excellent in operability. In addition,compound (1) of the present invention or a salt thereof has excellentchemical stability.

Compound (1a) of the present invention can be suitably used as astarting material for producing compound (1b).

Use of compound (1) of the present invention or a salt thereof enablescompositions to be provided in various forms that express drug efficacyequal to tolvaptan, which is an effective drug.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the change in serum concentration of tolvaptanin female rats after rapid tail-vein administration of a solution ofcompound (1b) at a dose such that 1 mg of tolvaptan is produced per kgof body weight.

FIG. 2 is a graph showing the change in serum concentration of tolvaptanin female rats after oral administration of a solution of compound (1b)at a dose such that 1 mg of tolvaptan is produced per kg of body weight.

BEST MODE FOR CARRYING OUT THE INVENTION

Examples, test examples and preparation examples are given below toillustrate the present invention in further detail, but the scope of theinvention is not limited to these examples.

Example 1

A 1.0 g quantity of tolvaptan (compound (2)) and 460 mg of 1H-tetrazolewere dissolved in 30 ml of methylene chloride, and 1.2 g of dibenzyldiisopropylphosphoramidite was added dropwise to this solution at roomtemperature with stirring. The mixture was then stirred for 2 hours atthe same temperature.

The obtained reaction mixture was cooled to −40° C., and 6 ml ofmethylene chloride solution of 920 mg of metachloroperbenzoic acid wasadded dropwise thereto. The mixture was then stirred at the sametemperature for 30 minutes, and at 0° C. for 30 minutes. The reactionmixture was washed with an aqueous sodium thiosulfate solution andsaturated aqueous sodium bicarbonate, and then dried over anhydroussodium sulfate. The obtained reaction mixture was filtered andconcentrated, and the residue was purified by silica gel columnchromatography (eluent: n-hexane:ethyl acetate=1:1) to give 1.5 g ofamorphous compound (1a-1) (yield 97.2%).

NMR (DMSO-d₆, 100° C.) δ ppm; 9.86 (1H, br s), 7.56 (1H, s), 7.50-7.10(17H, m), 7.00-6.80 (2H, m), 5.60-5.50 (1H, m), 5.15-5.00 (4H, m),5.00-2.75 (2H, m), 2.36 (3H, s), 2.34 (3H, s), 2.10-1.70 (4H, m)

Example 2

A 4.5 g quantity of tolvaptan (compound (2)) and 2.2 g of 1H-tetrazolewere dissolved in 120 ml of methylene chloride, and a solution of 4.0 gof di t-butyl diisopropylphosphoramidite dissolved in 10 ml of methylenechloride was added dropwise to this solution with ice-cooling andstirring. The mixture was then stirred at room temperature for 2 hours.

The obtained reaction mixture was cooled to −40° C., and 20 ml ofmethylene chloride solution of 4.0 g of metachloro perbenzoic acid wasadded dropwise thereto. The mixture was then stirred at the sametemperature for 30 minutes, and at 0° C. for 40 minutes. The reactionmixture was washed with an aqueous sodium thiosulfate solution andsaturated aqueous sodium bicarbonate, and then dried over anhydroussodium sulfate. The obtained reaction mixture was filtered andconcentrated, and the residue was purified by silica gel columnchromatography (eluent: hexane:ethyl acetate=1:1) to give 3.0 g ofamorphous compound (1a-2) (yield 46.7%).

NMR (DMSO-d₆) δ ppm; 10.50-10.20 (1H, m), 8.00-6.50 (10H, m), 5.55-5.20(1H, m), 4.90-4.50 (1H, m), 2.85-2.60 (1H, m), 2.40-2.20 (6H, m),2.20-1.60 (4H, m), 1.60-1.30 (18H, m)

Example 3

A 5.3 g quantity of compound (1a-1) was dissolved in 100 ml of ethanol,and, using 2 g of 5% palladium-carbon as a catalyst, the solution wassubjected to catalytic reduction at room temperature and atmosphericpressure for 10 minutes. The catalyst was removed from the solution byfiltration, and the obtained filtrate was concentrated (4.2 g). Theobtained residue was crystallized from methanol/water. The crystals werecollected by filtration and then dried under reduced pressure(diphosphorus pentoxide) to give 3.5 g of white powdery compound (1b)(yield 88.5%).

Melting point: 150 to 152° C.

NMR (DMSO-d₆-D₂O, 100° C.) δ ppm; 7.50-6.70 (10H, m), 5.50-5.40 (1H, m),5.00-2.50 (2H, m), 2.37 (6H, s), 2.40-1.50 (4H, m)

Example 4

A 3.0 g quantity of compound (1a-2) was dissolved in 100 ml of methylenechloride, and a solution of 10 ml of trifluoroacetic acid dissolved in 5ml of methylene chloride was added dropwise to this solution withice-cooling and stirring. The mixture was then stirred at the sametemperature for 2 hours. The solvent was removed from the solution. Theobtained residue was redissolved in methylene chloride, and thenconcentrated. The obtained residue was crystallized from methanol/water.The crystals were collected by filtration and then dried under reducedpressure (diphosphorus pentoxide) to give 1.9 g of white powderycompound (1b) (yield 76.8%).

Example 5

A 240 ml quantity of 1,2-dimethoxyethane (DME) and 84 ml oftriethylamine (0.60 mol, 9 equivalents) were added to 30 g (66 mmol) oftolvaptan (compound (2)), and the mixture was cooled under a nitrogenstream to −15° C. A 19 ml quantity (0.20 mol, 3 equivalents) ofphosphorus oxychloride (POCl₃) was added dropwise to the obtainedmixture at an internal temperature of no more than −12° C., and stirringwas performed at −12° C. for 2 hours. A 200 ml quantity of 5 N sodiumhydroxide aqueous solution was added to 1 kg of crashed ice, and theabove reaction mixture were added in small portions thereto withstirring. To the obtained mixture was added 500 ml of toluene. Themixture was heated to 50° C. and then separated into an aqueous layerand a toluene layer. A 500 ml quantity of toluene was added again to theaqueous layer, stirring was performed at 50° C., and the mixture wasthen separated into an aqueous layer and a toluene layer. The aqueouslayer was cooled to 10° C., 80 ml of 6 N hydrochloric acid was addedthereto, and extraction was performed with 500 ml of ethyl acetatetwice. The extract was dried over sodium sulfate and filtered, and thefiltrate was concentrated. The concentrate was dried under reducedpressure at room temperature to give 34 g of amorphous compound (1b).

Yield: 97%

Example 6 Production of Calcium Salt of Compound (1b)

(1) A 2.6 g quantity (5.0 mmol) of compound (1b) was dissolved in 25 mlof isopropyl alcohol, and 2.2 ml of 5 N sodium hydroxide aqueoussolution was added thereto at room temperature. The obtained mixture wasconcentrated under reduced pressure. To the residue was added 30 ml ofwater to dissolve the solid content, and an aqueous solution of 0.61 g(5.5 mmol) of calcium chloride was then added thereto. The precipitatedsolids were collected by filtration, washed with water, and hotair-dried at 60° C. to give 2.2 g of white powdery calcium salt ofcompound (1b).

Yield: 78%

¹H-NMR (DMSO-d₆, 100° C.) δ ppm: 1.3-2.4 (10H, m), 2.8-4.5 (2H, m),5.2-5.8 (1H, m), 6.4-8.1 (10H, m), 9.0-10.2 (1H, m)

(2) A 280 mg quantity (0.53 mmol) of compound (1b) was dissolved in amixed solution of 2 ml of methanol and 1 ml of water, and 43 mg (0.58mmol) of calcium hydroxide was then added thereto. The mixture wasstirred at room temperature for 1 hour. The precipitated solids werecollected by filtration. The filtered material was suspended inmethanol, stirred with heating, and then hot-filtered. The filtrate wasconcentrated, and the residue was recrystallized from methanol to give75.4 mg of white powdery calcium salt of compound (1b).

Yield: 25%

Melting point: 263 to 265° C.

Example 7 Production of Magnesium Salt of Compound (1b)

(1) A 1.0 g quantity (1.9 mmol) of compound (1b) was dissolved in 15 mlof methanol, and 0.76 ml of 5 N sodium hydroxide aqueous solution wasadded thereto. The mixture was concentrated under reduced pressure. Theresidue was dissolved in 10 ml of methanol, and 3 ml of methanolsolution of 0.18 g of magnesium chloride was added to the obtainedsolution at room temperature. Precipitated insoluble matter (NaCl) wasremoved by filtration, and the filtrate was concentrated. To the residuewas added 10 ml of water, and stirring was performed with heating. Themixture after stirring was allowed to cool to room temperature. Theinsoluble matter was then collected by filtration, washed with water,and dried under reduced pressure at 60° C. to give 400 mg of whitepowdery magnesium salt of compound (1b)

Yield: 38%

¹H-NMR (DMSO-d₆, 100° C.) δ ppm: 1.4-2.4 (10H, m), 2.8-4.5 (2H, m),5.3-5.5 (1H, m), 6.4-7.8 (10H, m), 9.7 (1H, br).

(2) A 282 mg quantity (0.53 mmol) of compound (1b) was dissolved in 2 mlof methanol, and 41 mg (0.70 mmol) of magnesium ethoxide was addedthereto with ice-cooling. To the obtained mixture were further added 2ml of ethanol and an aqueous suspension (0.5 ml) of 36 mg (0.58 mmol) ofmagnesium hydroxide, and stirring was performed at room temperature for1 hour. The insoluble matter was removed by filtration, and the filtratewas allowed to stand overnight. The precipitated solids were collectedby filtration and then dried under reduced pressure to give 24.9 mg ofwhite powdery magnesium salt of compound (1b).

Yield: 11%

Melting point: 250 to 252° C.

Example 8 Production of Monosodium Salt of Compound (1b)

A 0.5 ml quantity of 1 N sodium hydroxide aqueous solution and 1 ml ofwater were added to a methanol solution (2 ml) of 266 mg (0.5 mmol) ofcompound (1b) with ice-cooling, and the obtained solution was stirred atroom temperature for 1 hour. The reaction mixture was concentrated underreduced pressure, and the residue was recrystallized from methanol-waterto give 45.2 mg of white powdery monosodium salt of compound (1b).

Yield: 16%

Melting point: 235 to 238° C.

Example 9 Production of Disodium Salt of a Compound (1b)

A 1.0 ml quantity of 1 N sodium hydroxide aqueous solution was added toa methanol solution (2 ml) of 276 mg (0.52 mmol) of compound (1b) withice-cooling, and the obtained mixture was stirred for 5 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was recrystallized from acetone-water to give 221 mg of whitepowdery disodium salt of compound (1b).

Yield: 73%

Melting point: 250 to 252° C.

Example 10 Production of diammonium salt of compound (1b)

A 1.0 ml quantity of 25% aqueous ammonia solution was added to amethanol solution (2 ml) of 271 mg (0.51 mmol) of compound (1b) withice-cooling, and the obtained mixture was stirred for 10 minutes. Thereaction mixture was concentrated under reduced pressure, and theresidue was recrystallized from methanol-water to give 104 mg of whitepowdery diammonium salt of compound (1b).

Yield: 36%.

Melting point: 195 to 198° C.

Example 11 Production of Monopotassium Salt of Compound (1b)

A 0.5 ml quantity of 1 N potassium hydroxide aqueous solution was addedto a methanol solution (2 ml) of 276 mg (0.52 mmol) of compound (1b)with ice-cooling, and the obtained mixture was stirred for 10 minutes.The reaction mixture was concentrated under reduced pressure, and theresidue was recrystallized from isopropyl alcohol to give 110.6 mg ofwhite powdery monopotassium salt of compound (1b).

Yield: 37%

Melting point: 200 to 203° C.

Example 12 Production of Dipotassium Salt of Compound (1b)

A 1.0 ml quantity of 1 N potassium hydroxide aqueous solution was addedto a methanol solution (2 ml) of 276 mg (0.52 mmol) of compound (1b)with ice-cooling, and the obtained mixture was stirred for 5 minutes.The reaction mixture was concentrated under reduced pressure, anddiethyl ether was added to the residue. The insoluble matter wascollected by filtration and then dried to give 273.9 mg of white powderydipotassium salt of compound (1b).

Yield: 86%

Melting point: 255 to 265° C. (decomposition)

Example 13 Production of Zinc Salt of Compound (1b)

A 1.0 g quantity (1.9 mmol) of compound (1b) was dissolved in 15 ml ofmethanol, and 0.76 ml of 5 N sodium hydroxide aqueous solution was addedto this solution. The mixture was concentrated under reduced pressure.The obtained residue was dissolved in 10 ml of methanol, and 3 ml ofmethanol solution of 259 mg of zinc chloride was added thereto at roomtemperature. Precipitated insoluble matter (NaCl) was removed byfiltration, and the filtrate was concentrated. To the obtained residuewas added 10 ml of water, and stirring was performed with heating. Themixture was then allowed to cool to room temperature. The insolublematter was collected by filtration, washed with water, and dried underreduced pressure at 60° C. to give 900 mg of white powdery zinc salt ofcompound (1b).

Yield: 80%

Melting point: 235 to 239° C. (decomposition)

¹H-NMR (DMSO-d₆, 100° C.) δ ppm: 1.3-2.4 (10H, m), 2.8-4.5 (2H, m),5.3-5.7 (1H, m), 6.6-7.7 (10H, m), 9.7 (1H, br)

Example 14 Production of Ethylenediamine Salt of Compound (1b)

A 0.074 ml quantity (1.1 mmol) of ethylenediamine was added to anethanol solution (10 ml) of 600 mg (1.1 mmol) of compound (1b). Theobtained reaction mixture was concentrated under reduced pressure, andthe residue was recrystallized from isoporpyl alcohol to give 250 mg ofwhite powdery ethylenediamine salt of compound (1b).

¹H-NMR (DMSO-d₆, 100° C.) δ ppm: 1.5-2.0 (3H, m), 2.1-2.4 (7H, m), 2.77(4H, s), 2.8-4.3 (2H, m), 5.3-5.5 (1H, m), 6.6-6.9 (1H, m), 6.9-7.2 (2H,m), 7.2-7.5 (5H, m), 7.58 (2H, d, J=7.6 Hz), 9.80 (1H, br)

Example 15 Production of Diethanolamine Salt of Compound (1b)

A 0.14 ml quantity (2.3 mmol) of ethanolamine was added to an isopropylalcohol solution (6 ml) of 600 mg (1.1 mmol) of compound (1b). A 6 mlquantity of isopropyl alcohol was added to the obtained mixture,dissolution was performed with heating, and recrystallization fromisopropyl alcohol gave 280 mg of white powdery diethanolamine salt ofcompound (1b).

¹H-NMR (DMSO-d₆, 100° C.) δ ppm: 1.4-2.0 (3H, R), 2.2-2.5 (7H, m), 2.75(4H, t, J=5.5 Hz), 3.52 (4H, t, J=5.5 Hz), 2.8-4.3 (2H, m), 5.3-5.5 (1H,m), 6.7-6.9 (1H, m), 6.9-7.2 (2H, m), 7.2-7.4 (4H, m), 7.42 (1H, d,J=7.7 Hz), 7.57 (2H, d, J=6.5 Hz), 7.58 (2H, d, J=7.6 Hz), 9.80 (1H, br)

Example 16

A 1.3 ml quantity (6.6 mmol) of diphenyl phosphite was added to apyridine solution (10 ml) of 1.0 g (2.2 mmol) of tolvaptan (compound(2)) with ice-cooling. The obtained mixture was stirred at 0° C. for 30minutes, and then at room temperature for 30 minutes. To the reactionmixture was added 0.58 ml of ethanol, and stirring was performed at roomtemperature for 30 minutes. To this mixture was added 1 N hydrochloricacid, and extraction was performed with ethyl acetate. The ethyl acetatelayer was washed with a saturated aqueous sodium hydrogen carbonatesolution, dried over sodium sulfate, and then filtered, and the filtratewas concentrated. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=27:73→0:100). The purifiedproduct was concentrated under reduced pressure, and the residue wasdissolved in a mixed solvent of 10 ml of acetonitrile and 10 ml of waterand then freeze-dried to give 450 mg of white amorphous solid targetcompound.

Yield: 38%

¹H-NMR (Toluene-d₈, 100° C.) δ ppm: 1.0-1.1 (3H, m), 1.4-1.9 (4H, m),2.31 (3H, s), 2.42 (3H, s), 2.0-4.0 (2H, m), 3.7-4.1 (2H, m), 5.5 (0.5H,d, J=4.8 Hz), 6.4-7.5 (10H, m), 7.8 (0.5H, d, J=8.6 Hz)

Example 17

A pyridine solution (50 ml) of 10.0 g (22 mmol) of tolvaptan (compound(2)) was ice-cooled, and 13 ml (66 mmol) of diphenyl phosphite wasslowly added thereto under a nitrogen atmosphere. The obtained mixturewas stirred at room temperature for 30 minutes. To this mixture wasadded 4.5 ml of methanol, and stirring was performed at room temperaturefor 30 minutes. The obtained reaction mixture was added with ice-coolingto 325 ml of 2 N hydrochloric acid, and extraction was performed withethyl acetate. The ethyl acetate layer was washed with saturated brine,dried over sodium sulfate, and then filtered, and the filtrate wasconcentrated. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:methanol=100:0→93:7). The purified productwas concentrated under reduced pressure to give 10.5 g of whiteamorphous solid target compound.

Yield: 91%

¹H-NMR (Toluene-d₈, 100° C.) δ ppm: 1.5-2.0 (4H, m), 2.41 (3H, s), 2.49(3H, s), 3.0-4.2 (2H, m), 5.5 (0.5H, d, J=4.8 Hz), 5.5-5.8 (1H, m), 6.6(1H, d, J=8.3 Hz), 6.7-6.9 (1H, m), 6.9-7.2 (6H, m), 7.3-7.5 (2H, m),7.81, 7.84 (0.5H, d, J=8.1 Hz)

Example 18

A 0.1 ml quantity of water and 254 mg (1.0 mmol) of iodine were added toa pyridine solution (5 ml) of 500 mg (0.95 mmol) of the compound ofExample 17, and the obtained mixture was stirred at room temperature for30 minutes. To this mixture was added 2 ml of triethylamine, andconcentration under reduced pressure was performed. A 20 ml quantity oftoluene was added to the residue, and concentration under reducedpressure was performed. Water was added to the residue, and washing wasperformed with a mixed solvent of ethyl acetate and diethyl ether. Tothe aqueous layer was added 1 N hydrochloric acid, and extraction wasperformed with ethyl acetate. The ethyl acetate layer was dried oversodium sulfate and then filtered, and the filtrate was concentrated. Theobtained residue was purified by silica gel column chromatography(dichloromethane:methanol=90:10→50:50). The purified product wasconcentrated under reduced pressure, and the residue was dissolved in 30ml of water. The obtained solution was filtered through celite, and thefiltrate was freeze-dried to give 140 mg of white amorphous solid targetcompound.

¹H-NMR (Toluene-d₈, 100° C.) δ ppm: 1.4-2.0 (4H, m), 2.33 (3H, s), 2.34(3H, s), 2.5-4.5 (5H, m), 5.4-5.7 (2H, m), 6.5 (2H, d, J=7.9 Hz), 6.7(2H, d, J=7.9 Hz), 6.8-7.2 (5H, m), 7.2-7.4 (2H, m), 7.55 (1H, s)

Example 19

A 64 mg quantity (1.0 mmol) of sulfur was added to a pyridine solution(5 ml) of 500 mg (0.9 mmol) of the compound of Example 17, and theobtained mixture was stirred at room temperature for 2 hours. To thismixture was added 1 ml of triethylamine, and concentration under reducedpressure was performed. A 10 ml quantity of toluene was added to theobtained residue, and concentration under reduced pressure wasperformed. Water was added to the residue for dissolution, andfiltration was performed using celite. To the filtrate was added 1 Nhydrochloric acid, and extraction was performed with ethyl acetate. Theethyl acetate layer was dried over sodium sulfate and then filtered, andthe filtrate was concentrated. Water was added to the obtained residue,and the insoluble matter was collected by filtration and then dried togive 300 mg of white powdery target compound.

¹H-NMR (Toluene-d₈, 100° C.) δ ppm: 1.1-2.0 (4H, m), 2.2-2.5 (6H, m),3.5 (3H, dd, J=13.9, 14.9 Hz), 2.5-5.0 (2H, m), 3.5-5.7 (1H, m), 6.4-7.5(10H, m)

Example 20

A 0.5 ml quantity of water, 0.5 ml of carbon tetrachloride, 0.5 ml oftriethylamine, and 0.072 ml (1.2 mmol) of ethanolamine were added to anacetonitrile solution (5 ml) of 500 mg (0.95 mmol) of the compound ofExample 17, and the obtained mixture was stirred at room temperature for10 minutes. Water was added to this mixture, and extraction wasperformed with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried over sodium sulfate, and then filtered, and thefiltrate was concentrated. The obtained residue was purified by silicagel column chromatography (ethyl acetate:methanol=100:0→80:20). Thepurified product was concentrated under reduced pressure to give 540 mgof white amorphous solid target compound.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm: 1.6-2.3 (4H, m), 2.36 (6H, s), 2.7-3.1(2H, m), 2.5-4.5 (2H, m), 3.3-3.5 (2H, m), 3.65 (3H, dd, J=9.6, 11.2Hz), 4.0-4.3 (1H, m), 4.4-4.8 (1H, m), 5.3-5.7 (1H, m), 6.7-7.1 (2H, m),7.1-7.5 (5H, m), 7.57 (1H, s), 9.76 (1H, s)

Example 21

A 0.5 ml quantity of water, 0.5 ml of carbon tetrachloride, 0.5 ml oftriethylamine, and 0.119 ml (1.2 mmol) of methylamine (40% methanolsolution) were added to an acetonitrile solution (5 ml) of 500 mg (0.95mmol) of the compound of Example 17, and the obtained mixture wasstirred at room temperature for 10 minutes. Water was added to thismixture, and extraction was performed with ethyl acetate. The ethylacetate layer was washed with saturated brine, dried over sodiumsulfate, and then filtered, and the filtrate was concentrated. Theobtained residue was purified by silica gel column chromatography (ethylacetate:methanol=94:6→85:15). The purified product was concentratedunder reduced pressure to give 250 mg of white amorphous solid targetcompound.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm: 1.7-2.3 (4H, m), 2.37 (6H, s), 2.4-2.6(3H, m), 2.8-4.3 (2H, m), 3.63 (3H, t, J=10.7 Hz), 4.4-4.8 (1H, m),5.3-5.6 (1H, m), 6.6-7.1 (2H, m), 7.1-7.5 (5H, m), 7.58 (1H, s), 9.81(1H, s)

Example 22

A 0.5 ml quantity of water, 0.5 ml of carbon tetrachloride, 0.5 ml oftriethylamine, and 0.115 ml (1.2 mmol) of diethanolamine were added toan acetonitrile solution (5 ml) of 500 mg (0.95 mmol) of the compound ofExample 17, and the obtained mixture was stirred at room temperature for10 minutes. Water was added to this mixture, and extraction wasperformed with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, dried over sodium sulfate, and then filtered, and thefiltrate was concentrated. The obtained residue was purified by silicagel column chromatography (ethyl acetate:methanol=88:12→70:30). Thepurified product was concentrated under reduced pressure, and theresidue was recrystallized from water-containing methanol to give 250 mgof white powdery target compound.

¹H-NMR (DMSO-d₆, 100° C.) δ ppm: 1.6-2.2 (4H, m), 2.37 (6H, s), 3.0-3.2(4H, m), 3.5-3.7 (7H, m), 2.8-4.3 (2H, m), 4.1-4.4 (1H, m), 5.3-5.7 (1H,m), 6.7-7.1 (2H, m), 7.1-7.5 (7H, m), 7.5-7.7 (1H, m), 9.80 (1H, br)

Example 23

A 3.8 mg (20 mmol) quantity of diphenyl phosphite was added to apyridine solution (10 ml) of 3.0 g (6.7 mmol) of tolvaptan (compound(2)), and the obtained mixture was stirred at room temperature for 1hour. To this mixture was added 2 ml of water, and stirring wasperformed at room temperature for 30 minutes. The obtained reactionmixture was concentrated under reduced pressure, 1 N hydrochloric acidwas added to the residue, and extraction was performed with ethylacetate. The ethyl acetate layer was washed with saturated brine twice,dried over sodium sulfate, and then filtered, and the filtrate wasconcentrated. The obtained residue was purified by silica gel columnchromatography (ethyl acetate:methanol=100:0→50:50). The purifiedproduct was concentrated under reduced pressure. The residue wasdissolved in water, and the insoluble matter precipitated by adding 1 Nhydrochloric acid was collected by filtration and then dried to give0.83 g of white powdery target compound.

Yield: 24%

¹H-NMR (DMSO-d₆, 100° C.) δ ppm: 1.7-2.2 (4H, m), 2.35 (3H, s), 2.36(3H, s), 2.8-4.3 (2H, m), 5.4-5.6 (1H, m), 5.8 (0.5H, br), 6.7-7.4 (8H,m), 7.47 (1H, d, J=2.3 Hz), 7.55 (1H, s), 9.79 (1H, br)

Example 24

A 2.9 ml quantity of phosphorus trichloride was added under a nitrogenstream to tetrahydrofuran (THF) (29 ml). The obtained mixture wasice-cooled, and 6.1 ml (44 mmol) of triethylamine was added thereto.This mixture was cooled in an ice-methanol bath. A THF solution (120 ml)of 10.0 g (22 mmol) of tolvaptan (compound (2)) was then added dropwisethereto at an internal temperature of not more than −10° C., andstirring was performed at the same temperature for 2 hours. A 130 mlquantity of 1 N sodium hydroxide aqueous solution was added dropwise tothe obtained reaction mixture at an internal temperature of not morethan 0° C., 200 ml quantity of water was further added thereto, andwashing was performed with toluene twice. The obtained aqueous solutionwas cooled in an ice-methanol bath, 1 N HCl was added dropwise theretoat an internal temperature of not more than 0° C., and extraction wasperformed with ethyl acetate. The ethyl acetate layer was dried oversodium sulfate and then filtered, and the filtrate was concentrated togive 6.8 g of white amorphous solid target compound.

Yield: 60%

Example 25

quantity of 3.8 ml (20 mmol) of diphenyl phosphite was added to apyridine solution (10 ml) of 3.0 g (6.7 mmol) of tolvaptan (compound(2)), and the obtained mixture was stirred at room temperature for 1hour. To this mixture was added 5.2 ml (66.6 mmol) of methyl glycolate,and stirring was performed at room temperature for 12 hours. To thereaction mixture was added 50 ml of water, and extraction was performedwith ethyl acetate. The ethyl acetate layer was washed with 1 Nhydrochloric acid twice, dried over sodium sulfate, and then filtered,and the filtrate was concentrated. The obtained residue was purified bysilica gel column chromatography (n-hexane:ethyl acetate=50:50→0:100).The purified product was concentrated under reduced pressure to give0.79 g of white amorphous solid target compound.

Yield: 20%

¹H-NMR (Toluene-d₈, 100° C.) δ ppm: 1.6-2.2 (4H, m), 2.51 (3H, s), 2.60(3H, s), 3.2-4.4 (2H, m), 3.53 (3H, s), 4.43 (1H, s), 4.47 (1H, s), 5.87(0.5H, s), 5.9-6.1 (1H, m), 6.6-6.8 (1H, m), 6.8-7.0 (2H, m), 7.0-7.4(5H, m), 7.48 (1H, s), 7.63 (1H, s), 8.27 (0.5H, s).

Example 26

A 0.8 ml quantity of water was added to a pyridine solution (7.9 ml) of0.79 g (1.35 mmol) of the compound of Example 25. To the obtainedmixture was added with ice-cooling 0.34 g (2.7 mmol) of iodine, andstirring was performed at room temperature for 1 hour. To the reactionmixture was added 1 N hydrochloric acid, and extraction was performedwith ethyl acetate. The ethyl acetate layer was washed with saturatedbrine, dried over sodium sulfate, and then filtered, and the filtratewas concentrated. The obtained residue was dissolved in water and thenfreeze-dried to give 80 mg of white amorphous solid target compound.

Yield: 9.9%

¹H-NMR (DMSO-d₆, 100° C.) δ ppm: 1.7-2.3 (4H, m), 2.35 (3H, s), 2.36(3H, s), 2.8-4.3 (2H, m), 4.49 (2H, dd, J=1.7, 10.1 Hz), 5.4-5.6 (1H,m), 6.7-7.1 (2H, m), 7.1-7.5 (7H, m), 7.54 (1H, s), 9.79 (1H, br)

Example 27

A 3.0 g quantity (6.7 mmol) of tolvaptan (compound (2)) were added insmall portions to a pyridine solution (15 ml) of 3.8 ml (20 mmol) ofdiphenyl phosphite, and the obtained mixture was stirred at roomtemperature for 0.5 hours. To this mixture was added 2.8 ml (40 mmol) of3-hydroxypropionitrile, and stirring was performed at room temperaturefor 0.5 hours. To the obtained reaction mixture was added 1 Nhydrochloric acid, and extraction was performed with ethyl acetate. Theethyl acetate layer was washed with water, dried over sodium sulfate,and then filtered, and the filtrate was concentrated. The obtainedresidue was purified by silica gel column chromatography (ethylacetate:methanol=100:0→10:1). The purified product was concentratedunder reduced pressure to give 2.8 g of white amorphous solid targetcompound.

Yield: 75%

¹H-NMR (Toluene-d₈, 100° C.) δ ppm: 1.4-2.0 (6H, m), 2.33 (3H, s), 2.40(3H, s), 3.1-3.8 (4H, m), 5.40 (0.5H, d, J=3.1 Hz), 5.3-5.4 (1H, m),6.5-6.7 (1H, m), 6.7-6.9 (1H, m), 6.9-7.2 (6H, m), 7.2-7.5 (2H, m), 7.76(0.5H, d, J=8.5 Hz)

Example 28

A 0.115 g quantity (3.6 mmol) of sulfur was added to a pyridine solution(10 ml) of 1.0 g (1.8 mmol) of the compound of Example 27, and theobtained mixture was stirred at room temperature for 2 hours. To thismixture was added 1 N hydrochloric acid, and extraction was performedwith ethyl acetate. The ethyl acetate layer was dried over sodiumsulfate and then filtered, and the filtrate was concentrated. Theobtained residue was purified by silica gel column chromatography (ethylacetate:methanol=100:0→85:15). The purified product was concentratedunder reduced pressure to give 0.91 g of white amorphous solid targetcompound:

Yield: 85%

¹H-NMR (DMSO-d₆, 100° C.) δ ppm: 1.6-1.9 (3H, m), 2.0-2.3 (1H, m), 2.10(3H, m), 2.36 (6H, s), 2.3-4.2 (2H, m), 2.7-2.8 (2H, m), 3.9-4.2 (2H,m), 5.5-5.8 (1H, m), 6.7-6.9 (1H, m), 7.0-7.4 (7H, m), 7.4-7.5 (1H, m),7.56 (1H, s), 7.7-7.8 (0.3H, m), 8.5-8.6 (m, 0.7H), 9.76 (1H, br)

Example 29

A 300 mg quantity (0.5 mmol) of the compound of Example 28 was added to5 ml of 28% aqueous ammonia, and the obtained mixture was stirred atroom temperature for three days. To this mixture was added 1 Nhydrochloric acid. The precipitated solids were collected by filtrationand then dried to give 100 mg of white powdery target compound.

Yield: 37%

¹H-NMR (Pyridine-d₅-D₂O, 90° C.) δ ppm: 1.6-2.4 (4H, m), 2.43 (3H, s),2.53 (3H, s), 2.8-4.3 (2H, m), 5.1-5.4 (1H, m), 6.8-7.3 (6H, m), 7.4-7.7(2H, m), 7.7-8.1 (2H, m)

Example 30

A 0.62 ml quantity (6.6 mmol) of phosphorus oxychloride and 0.92 ml (6.6mmol) of triethylamine were added under a nitrogen stream totetrahydrofuran (THF) (5 ml). The obtained mixture was cooled in anice-methanol bath. A THF solution (10 ml) of 1.0 g (2.2 mmol) oftolvaptan (compound (2)) was then added dropwise thereto, and stirringwas performed at the same temperature for 30 minutes. To this mixturewere added 2.8 ml (20 mmol) of triethylamine and 1.1 ml (26.4 mmol) ofmethanol, and stirring was performed for 30 minutes. Water was added tothe obtained reaction mixture, and extraction was performed with ethylacetate. The ethyl acetate layer was dried over sodium sulfate and thenfiltered, and the filtrate was concentrated. The obtained residue waspurified by silica gel column chromatography (ethylacetate:methanol=100:0→80:20). The purified product was concentratedunder reduced pressure, and the residue was recrystallized fromwater-containing methanol to give 400 mg of white powdery targetcompound.

Yield: 33%

¹H-NMR (DMSO-d₆, 100° C.) δ ppm: 1.7-2.2 (4H, m), 2.36 (6H, s), 2.8-4.3(2H, m), 3.71 (6H, dd, J=10.2, 11.1 Hz), 5.5-5.6 (1H, m), 6.8-7.1 (2H,m), 7.1-7.5 (7H, m), 7.58 (1H, s), 9.80 (1H, br)

Test Example 1 Solubility of Compound (1b)

Compound (1b) as obtained in Example 3 or 4 was added in excess to 0.1 Nsodium phosphate buffer (pH 5, pH 6, pH 7, pH 8, pH 9, or pH 10), 0.1 NTris/HCl buffer (pH 8 or pH 9), 0.1 N sodium hydrogencarbonate/HClbuffer (pH 8) or 0.1 N sodium citrate buffer (pH 8), and then shaken atroom temperature for 16 days. If the test compound dissolved even afterabout 6 to about 8 w/v % had been added thereto, no further testcompound was added.

Each solution was filtered through a 0.45-μm filter, and then, under thefollowing HPLC conditions, the solubility of compound (1b) wasdetermined by absolute calibration.

HPLC Conditions

Detection: ultraviolet absorption photometer

-   -   (measurement wavelength: 254 nm)

Column: YMC(ODS) AM-302 (4.6×150 mm)

Column temperature: constant temperature of approximately 2′5° C.Eluate: acetonitrile/water/phosphoric acid=450/550/1Flow rate: 1 ml/minInjection volume: 10 μl

TABLE 1 Solubility of compound (1b) in buffer solution (roomtemperature) Solubility of Solvent pH before pH after compound (1b) (100mM buffer) dissolution dissolution (w/v %) Sodium phosphate buffer 5 3.00.58 6 3.0 1.31 7 3.1 0.76 8 3.3 at least 7.1* 9 3.3 at least 7.4* 103.4 at least 6.5* Tris buffer 8 2.9 0.74 9 3.4 at least 6.3* Citric acidbuffer 8 4.2 at least 8.3* Sodium hydrogencarbonate 8 3.1 at least 7.1*buffer *Sample having a solubility so high that crystals could not beadded in excess

Test Example 2 Solubility of Salt of Compound (1)

A suitable amount of test compound is added to a test tube, and 2.5 mlof water is added thereto. After shaking at 37° C. for 30 minutes, themixture is filtered through a 0.45-μm membrane filter, and 0.5 ml of thefiltrate is accurately weighed. Mobile phase is added thereto to makeexactly 50 ml, preparing a test solution (dilution ratio: 100-fold).Approximately 5 mg of free-form authentic sample is accurately weighed,and acetonitrile is added thereto to make exactly 50 ml. A 2 ml of thisliquid is accurately weighed, and mobile phase is added thereto to makeexactly 20 ml, preparing a standard solution (equivalent to 10 μg/ml).By liquid chromatography under the following conditions, 20 μl of boththe test solution and standard solution are tested to obtain the peakareas At and As of the test solution and standard solution.

Concentration(μg/ml)=Ws/5×10×At/As×100=Ws×At/As×200

Ws: weighed amount of authentic sample (mg)

Test Conditions

-   -   Detection: ultraviolet absorption photometer        -   (measurement wavelength: 254 nm)    -   Column: TOSOH TSKgel ODS-80Ts (0.46 cm×15 cm)    -   Column temperature: constant temperature of approximately 40° C.    -   Mobile phase: water/acetonitrile/trifluoroacetic acid=500/500/1    -   Flow rate: 1 ml/min

TABLE 2 Test compound (Example No.) Solubility (w/v %) 5 >0.1 7 >0.18 >0.1 11 >0.1 16 >0.1 17 >0.1 20 >0.1 31 >0.1

Test Example 3 Solubility of Tolvaptan

Tolvaptan was added in excess to Britton-Robinson buffer (pH 2, pH 7, orpH 12) or purified water, and then shaken at 25° C.±1° C. for 4 hours.Each solution was filtered through a filter, and then, using HPLC, thesolubility of tolvaptan was quantified by absolute calibration.

TABLE 3 Solubility of tolvaptan in Britton- Robinson buffer and purifiedwater Solvent Solubility of tolvaptan (w/v %) Water 0.00002 pH 2 0.00002pH 7 0.00003 pH 12 0.00002

Test Example 4 Serum Concentration of Tolvaptan in Female Rats afterTail-Vein Administration of a Compound (1b) Solution Experiment Method

A solution of compound (1b) (equivalent to 1 mg of tolvaptan per ml ofsolution) was prepared.

TABLE 4 Formulation (in 1 ml) Amount (mg) Compound (1b) 1.0* Sodiumdihydrogen- 0.79 phosphate•dihydrate Mannitol 50   Sodium hydroxideSuitable amount to adjust to pH 7.0 Water for Injection Suitable amount*Amount equivalent to 1.0 mg of tolvaptan per ml of solution

Preparation Method

A 79 mg quantity of sodium dihydrogenphosphate•dihydrate and 5 g ofmannitol were dissolved in about 90 ml of water for injection. A sodiumhydroxide solution was added thereto, and a solution of pH 7 wasprepared. Compound (1b) equivalent to 100 mg of tolvaptan was dissolvedin this solution. A sodium hydroxide solution was added thereto, and thepH was adjusted to 7. Injection solvent was added to the obtainedsolution to make 100 ml, and sterile filtration was performed with a0.2-μm filter to prepare a solution of compound (1b) (equivalent to 1 mgof tolvaptan per ml of solution).

This solution was rapidly administered to female rats via the tail veinat a dose such that 1 mg of tolvaptan is produced per kg of body weight.From time to time, blood was collected from the jugular vein under lightethyl ether anesthesia, and serum concentration of tolvaptan wasdetermined by high-speed liquid chromatography (HPLC).

The results are shown in FIG. 1.

Tolvaptan was initially detected five minutes after the intravenousadministration of a solution of compound (1b) to female rats. Thisindicates that compound (1b) is rapidly hydrolyzed into tolvaptan inrats.

Test Example 5 Serum Concentration of Tolvaptan in Female Rats afterOral Administration of a Compound (1b) Solution Experiment Method

A solution of compound (1b) (equivalent to 0.4 mg of tolvaptan per ml ofsolution) was prepared.

TABLE 5 Formulation (in 1 ml) Amount (mg) Compound (1b) 0.4* Sodiumhydrogencarbonate 2   Sodium hydroxide Suitable amount (pH 9.1) Waterfor Injection Suitable amount *Amount equivalent to 0.4 mg of tolvaptanper ml of solution

Preparation Method

A 1 g quantity of sodium hydrogencarbonate was dissolved in about 400 mlof water for injection. A sodium hydroxide solution was added thereto toadjust the pH to 9.0, and water for injection was added thereto,preparing 500 ml of 0.2% sodium hydrogencarbonate solution. An 89 μlquantity of 1 N sodium hydroxide solution and compound (1b) equivalentto 20 mg of tolvaptan were added to about 40 ml of this 0.2% sodiumhydrogencarbonate solution and dissolved. A 0.2% sodiumhydrogencarbonate solution was further added thereto to make 50 ml,thereby preparing a solution of compound (1b) (equivalent to 0.4 mg oftolvaptan per ml of solution). The pH of this solution was 9.1. Thissolution is called “Solution A” hereinafter.

A spray-dried tolvaptan powder equivalent to 60 mg of tolvaptan, whichwas prepared in a similar manner to Example 3 of JP1999-21241-A, wassuspended in 50 ml of water for injection in a porcelain mortar. Thissuspension was diluted three-fold with water for injection, preparing asuspension of spray-dried powder equivalent to 0.4 mg of tolvaptan perml of suspension. This suspension is called “Suspension B” hereinafter.

The following tests were performed in order to examine the oralabsorption characteristics of Solution A and Suspension B. Wistar femalerats (body weight about 160 g) which had been fasted for about 18 hourswere used as test animals. Solution A and Suspension B were eachadministered by forced oral administration using a sonde for oraladministration at a dose of 2.5 ml/kg of body weight, producing 1 mg oftolvaptan per kg of body weight. The blood samples were collected fromthe jugular vein under light ethyl ether anesthesia periodically afterdosing, and the serum concentrations of tolvaptan were determined byusing HPLC-MS/MS (Waters).

The obtained results are shown in FIG. 2 and Table 6. FIG. 2 shows theserum concentration-time profiles of tolvaptan after an oraladministration of Solution A and suspension B (n=4). Table 6 shows themean of the pharmacokinetic parameter values (n=4). The parameters inTable 6 have the following meanings.

-   AUC_(8hr): area under the serum concentration-time curve for up to 8    hours after administration (ng·hr/ml)-   AUC_(∞): area under the serum concentration-time curve for up to an    infinite time after administration (ng·hr/ml)-   C_(max): maximum serum concentration (ng/ml)-   T_(max): time to reach the maximum serum concentration (hr)

As a result, it was confirmed that that the solution of compound (1b)(Solution A) takes a shorter time to reach the maximum serumconcentration than the suspension of spray-dried tolvaptan (SuspensionB), and also leads to greater maximum serum concentration (C_(max)) andlarger areas under the serum concentration-time curve (AUC_(8hr),AUC_(∞)).

TABLE 6 AUC_(8 hr) C_(max) T_(max) AUC_(∞) (ng · hr/mL) (ng/mL) (hr) (ng· hr/mL) Solution A 217.5 61.0 1.3 230.1 Suspension B 73.2 26.4 1.5 76.1

These results revealed that when administered in vivo, the compound ofthe present invention, compound (1b) in particular, increases absorptioneven more than conventional absorption improvement by amorphization, andconsequently improves bioavailability of tolvaptan.

Preparation Example 1

A 79 mg quantity of sodium dihydrogenphosphate•dihydrate and 5 g ofmannitol were dissolved in about 90 ml of injection solvent. A sodiumhydroxide solution was added thereto, preparing a solution of pH 7.Compound (1b) equivalent to 100 mg of tolvaptan was added to thissolution. A sodium hydroxide solution was added thereto, adjusting thepH to 7. Injection solvent was added to the obtained solution to make100 ml, and sterile filtration was performed using a 0.2-μm filter togive an injection of the present invention containing compound (1b)(equivalent to 1 mg of tolvaptan per ml of injection).

Preparation Example 2

A 79 mg of sodium dihydrogenphosphate•dihydrate and 5 g mannitol weredissolved in about 90 ml of injection solvent. A sodium hydroxidesolution was added thereto, preparing a solution pH of 7.5. Compound(1b) equivalent to 10 mg of tolvaptan was dissolved in the solution.Injection solvent was added to the obtained solution to make 100 ml, andsterile filtration was performed with a 0.2-μm filter to prepare aninjection of the present invention containing compound (1b) (equivalentto 0.1 mg tolvaptan per ml of injection).

Preparation Example 3

A 380 mg quantity of trisodium phosphate•dodecahydrate and g of mannitolwere dissolved in about 90 ml of injection solvent. Compound (1b)equivalent to 100 mg, 300 mg or 1000 mg of tolvaptan was dissolved inthe obtained solution. When dissolving compound (1b) equivalent to 1000mg of tolvaptan, a sodium hydroxide solution was added to improve thesolubility. The pH of each obtained solution was adjusted to 8 to 9 withsodium hydroxide or hydrochloric acid, and an injection solvent wasadded thereto to make 100 ml. The obtained solution was sterile-filteredthrough a 0.2-μm filter, preparing injections of the present inventioncontaining compound (1b) (equivalent to 1 mg, 3 mg or 10 mg of tolvaptanper ml of injection).

1. A benzoazepine compound represented by general formula (1)

or a salt thereof, wherein R represents a hydrogen atom, a hydroxy groupoptionally protected with a protecting group, a mercapto groupoptionally protected with a protecting group, or an amino groupoptionally protected with one or two protecting groups; R¹ represents ahydrogen atom or a hydroxy-protecting group; and X represents an oxygenatom or a sulfur atom.
 2. A benzoazepine compound according to claim 1or a salt thereof, wherein X is an oxygen atom.
 3. A benzoazepinecompound according to claim 1 or 2, or a salt thereof, wherein R is ahydroxy group optionally protected with a protecting group.
 4. Abenzoazepine compound according to claim 1 or 2, or a salt thereof,wherein R is a hydrogen atom, a mercapto group optionally protected witha protecting group, or an amino group optionally protected with one ortwo protecting groups.
 5. A benzoazepine compound according to any oneof claims 1, 2, 3 and 4, or a salt thereof, wherein R¹ is ahydroxy-protecting group.
 6. A benzoazepine compound according to anyone of claims 1, 2, 3 and 4, or a salt thereof, wherein R¹ is a hydrogenatom.
 7. A benzoazepine compound according to claim 1 or a salt thereof,wherein X is a sulfur atom.
 8. A benzoazepine compound according toclaim 1 or a salt thereof, wherein X is an oxygen atom, R is a hydroxygroup, and R¹ is a hydrogen atom.
 9. A pharmaceutical compositioncomprising a benzoazepine compound of claim 1 or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablediluent and/or carrier.
 10. A pharmaceutical composition according toclaim 9, for use as a vasodilator, hypotensor, aquaretic agent, PKD, orplatelet aggregation inhibitor.
 11. An aqueous solution compositioncomprising a benzoazepine compound of claim 1 or a pharmaceuticallyacceptable salt thereof.
 12. An aqueous solution composition accordingto claim 11, comprising a benzoazepine compound of claim 1 or apharmaceutically acceptable salt thereof, together with a buffer,isotonizing agent and injection solvent, and which is in the form of aninjection.
 13. An aqueous solution composition according to claim 12,further comprising a pH adjuster.